TGF-β1

SAN DIEGO, Oct. 22, 2024 (GLOBE NEWSWIRE) -- Gyre Therapeutics, Inc. (“Gyre”) (Nasdaq: GYRE), a self-sustainable, commercial-stage biotechnology company with clinical development programs focusing on a variety of chronic organ diseases, today announced that the last patient in Gyre Pharmaceuticals’ pivotal Phase 3 trial in the People’s Republic of China (“PRC”) evaluating F351 (hydronidone) for Chronic Hepatitis B (“CHB”)-associated liver fibrosis has completed the 52-week study. Gyre Pharmaceuticals expects to report topline data from this trial by the first quarter of 2025. “The final patient completing our pivotal F351 Phase 3 trial marks an important milestone for Gyre and our development pipeline. We are grateful to the patients, researchers, trial investigators, and various teams who supported this trial and look forward to sharing data in the first quarter of 2025,” said Han Ying, Ph.D., CEO of Gyre Therapeutics. “Furthermore, we are excited to potentially use these results to spur initiation of our Phase 2 clinical trial in the United States evaluating F351 for Metabolic Dysfunction-Associated Steatohepatitis (“MASH”)-associated fibrosis in 2025.” The randomized, double-blind, placebo-controlled, multicenter Phase 3 trial (NCT05115942) enrolled 248 patients across 39 clinical research hospitals in the PRC. Patients were randomized 1:1 to receive either F351 or placebo in addition to entecavir antiviral basic therapy for CHB. The primary endpoint is a decrease in liver fibrosis (as measured by the Ishak Scoring System) by at least one stage after 52 weeks of treatment relative to baseline. China’s National Medical Products Administration (“NMPA”) designated F351 as a “Breakthrough Therapy” in 2021. About Hydronidone (F351) F351 is a structural analogue of the approved anti-fibrotic drug Pirfenidone (approved in the PRC for the treatment of idiopathic pulmonary fibrosis) and has been shown to inhibit in vitro both p38γ kinase activity and TGF-β1-induced excessive collagen synthesis in hepatic stellate cells (“HSCs”), which are recognized as critical event in the development and progression of fibrosis in the liver. This is further supported by its anti-proliferative effects on the HSCs in the liver. In vitro anti-fibrotic effects of F351 were also confirmed in several established in vivo models of liver fibrosis, such as CCI4-induced liver fibrosis mouse model, DMN-induced liver fibrosis rat model, and HSA-induced liver rat model, as well as mouse model of MASH fibrosis (CCI4+Western High Fat Diet). About Gyre Therapeutics Gyre Therapeutics is a biopharmaceutical company headquartered in San Diego, CA, with a primary focus on the development and commercialization of F351 (Hydronidone) for the treatment of MASH-associated fibrosis in the U.S. Gyre’s development strategy for F351 in MASH is based on the Company’s experience in MASH rodent model mechanistic studies and CHB-induced liver fibrosis clinical studies. Gyre is also advancing a diverse pipeline in the PRC through its indirect controlling interest in Gyre Pharmaceuticals, including ETUARY therapeutic expansions, F573, F528, and F230. About Gyre Pharmaceuticals Gyre Pharmaceuticals is a commercial-stage biopharmaceutical company committed to the research, development, manufacturing and commercialization of innovative drugs for organ fibrosis. Its flagship product, ETUARY (Pirfenidone capsule), was the first approved treatment for IPF in the PRC in 2011 and has maintained a prominent market share (2023 net sales of $112.1 million). In addition, Gyre Pharmaceuticals is evaluating F351 in a Phase 3 clinical trial in CHB-associated liver fibrosis in the PRC, which is expected to readout topline data by the first quarter of 2025. F351 received Breakthrough Therapy designation by the National Medical Products Administration’s Center for Drug Evaluation in March 2021. Gyre Pharmaceuticals is also developing treatments for COPD, PAH and ALF/ACLF. In October 2023, Gyre Therapeutics acquired an indirect majority interest in Gyre Pharmaceuticals (also known as Beijing Continent Pharmaceuticals Co., Ltd.). Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, which statements are subject to substantial risks and uncertainties and are based on estimates and assumptions. All statements, other than statements of historical facts included in this press release, are forward-looking statements, including statements concerning: the expectations regarding Gyre’s research and development efforts, timing of expected clinical readouts, including timing of topline data from Gyre Pharmaceuticals’ Phase 3 clinical trial evaluating F351 for the treatment of CHB-associated liver fibrosis in the PRC, and the initiation of Gyre’s Phase 2 trial in the U.S. for F351. In some cases, you can identify forward-looking statements by terms such as “may,” “might,” “will,” “objective,” “intend,” “should,” “could,” “can,” “would,” “expect,” “believe,” “design,” “estimate,” “predict,” “potential,” “plan” or the negative of these terms, and similar expressions intended to identify forward-looking statements. These statements reflect our plans, estimates, and expectations, as of the date of this press release. These statements involve known and unknown risks, uncertainties and other factors that could cause our actual results to differ materially from the forward-looking statements expressed or implied in this press release. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation: Gyre’s ability to execute on its clinical development strategies; positive results from a clinical trial may not necessarily be predictive of the results of future or ongoing clinical trials; the timing or likelihood of regulatory filings and approvals; competition from competing products; the impact of general economic, health, industrial or political conditions in the United States or internationally; the sufficiency of Gyre’s capital resources and its ability to raise additional capital. Additional risks and factors are identified under “Risk Factors” in Gyre’s Annual Report on Form 10-K for the year ended December 31, 2023 filed on March 27, 2024 and in other filings with the Securities and Exchange Commission. Gyre expressly disclaims any obligation to update any forward-looking statements whether as a result of new information, future events or otherwise, except as required by law. For Investors:Stephen Jasperstephen@gilmartinir.com

*仅供医学专业人士阅读参考 虽然已经是快10年前的事儿了，回想起屠呦呦因青蒿素拿下诺贝尔奖，奇点糕还不禁有些心潮澎湃。没想到拯救过百万人的抗疟“神药”青蒿素，它的衍生物到今天还能给我们带来新的惊喜，而且可能是一种重大疾病的0的突破。 今日，斯坦福大学科学团队在《细胞》杂志发文，研究者们开发了新的高通量多维度药物筛选技术，从约5000个化合物中找到了治疗心脏纤维化的破局新药，青蒿琥酯（ART）。 研究者们发现，青蒿琥酯以MD2为靶点，能够有效抑制心脏成纤维细胞中的纤维化基因表达，抑制其增殖、迁移和收缩，减少胶原蛋白沉积，改善心衰小鼠心脏功能。 心脏纤维化目前尚无临床治疗手段，考虑到青蒿琥酯已经在真实世界有大规模的应用，或许心脏纤维化药物很快就能迎来0的突破。 论文题图 所谓的纤维化，主要特征就是过度的细胞外基质（ECM）沉积，这会导致器官硬化和功能障碍。根据统计数据，发达国家的45%死亡人口可以归因于纤维化导致的器官衰竭。 如此严峻的形势，我们可用的药物却不多。FDA目前批准了两款可用于特发性肺纤维化治疗的药物，吡非尼酮和尼达尼布，但这两种药物对心脏纤维化却各有各的问题。前者作用机制不明，在临床试验中未能改善心功能，后者则具有潜在的心脏毒性、不适合用作慢性心脏病患者的长期治疗。 寻找心脏纤维化的潜力候选药物已经成为当务之急。 心脏纤维化是诸多疾病的常见合并症，包括缺血性心力衰竭（HF）、遗传性心肌病、糖尿病和衰老。在成年人体内，来自心外膜的常驻心脏成纤维细胞（CF）会在应激反应中被激活成为肌成纤维细胞（MyoFB），以表达αSMA和ACTA2为特征。 斯坦福的科学家们建立了一个人诱导多能干细胞（iPSC）为基础的多尺度药物发现平台，从iPSC中获得对纤维化刺激敏感的iPSC-CF，以ACTA2为标志检测MyoFB的激活。研究者对约5000个化合物进行了2次独立的高通量筛选，每个化合物测试7个不同剂量，并随后对iPSC衍生的心肌细胞（CM）和内皮细胞（EC）进行反筛选，排除具有潜在心血管毒性的化合物。 筛选平台工作流程 筛选得到的头号粽子选手就是青蒿琥酯（ART），EC50为2.1μM，10μM浓度时对iPSC-CM或iPSC-EC无毒性，50μM时仍不显著损害原代CF/CM/EC活力，可以说是很优秀了。 在多种促纤维化因子诱导的iPSC-CF模型和心脏纤维化患者体内分离的MyoFB中，青蒿琥酯都能有效地抑制MyoFB增殖和胶原分泌。而且青蒿琥酯预防和治疗都有效果。 青蒿琥酯能够抑制TGF-β1诱导的纤维化 接下来，研究者给小鼠做了主动脉缩窄术（TAC），用以模拟心脏肥厚早期阶段的纤维化。青蒿琥酯治疗能显著减少心肌中的胶原沉积和MyoFB标记基因表达。青蒿琥酯还显著改善了TAC导致的心衰相关心脏功能障碍。 在缺血再灌注（IR）模拟心肌梗死的小鼠模型中，青蒿琥酯也能显著改善心功能。 青蒿琥酯改善TAC诱导的心衰 研究者进一步探索了青蒿琥酯背后的分子机制。 青蒿琥酯的作用靶点为髓系分化因子2（MD2），抑制了MD2/TLR4信号通路，减轻了CF中的纤维化基因表达。 研究者发现，有诸多内源性配体能够激活MD2/TRL4，这一通路对心脏纤维化的发展至关重要，也能作为其他纤维化的通用靶点。 令人期待的是，青蒿琥酯已经广泛应用于治疗疟疾，用药人数超过百万，安全性很有保障。本研究中1μM青蒿琥酯即可显著降低MyoFB的激活，这一剂量低于抗疟治疗所需。 不过抗疟治疗中青蒿琥酯用药时间较短，如果用于心脏纤维化的治疗，其长期安全性还需要进一步探讨。 参考资料： [1]https://www.cell.com/cell/abstract/S0092-8674(24)01092-4 本文作者 | 代丝雨

Novel oncolytic immunotherapy being evaluated via IV and intratumoral delivery, both as monotherapy and in combination with checkpoint inhibitors PITTSBURGH, PA, USA I October 08, 2024 I KaliVir Immunotherapeutics, Inc. , a clinical-stage biotechnology company developing cutting-edge, multi-mechanistic oncolytic viral immunotherapy therapeutics, today announced that the first patient has been dosed in its STEALTH-001 study, a Phase 1/1b clinical trial of VET3-TGI for patients with incurable, advanced solid tumors. VET3-TGI is a novel oncolytic immunotherapy which is designed to target and selectively kill tumor cells while also expressing an immuno-stimulatory transgene payload consisting of interleukin-12 and a TGFbeta inhibitor. “The dosing of our first patient in the STEALTH-001 study marks a significant milestone for KaliVir and our innovative VET3-TGI program,” said James Burke, M.D., Chief Medical Officer of KaliVir Immunotherapeutics. “The unique engineering of this platform to selectively target the tumor even in the face of anti-viral immunity holds great promise in delivering potent immune stimulatory cargo intravenously in patients with advanced solid tumors. Both VET3-TGI monotherapy and combination with checkpoint inhibition will be explored in this initial study.” About the STEALTH-001 Clinical Trial STEALTH-001 (ClinicalTrials.gov No. NCT06444815) is a dose escalation and expansion study with VET3-TGI administered by direct injection into tumor(s) or by intravenous infusion. The dose escalation will determine the highest tolerated dose of VET3-TGI when injected directly into the tumor(s), given intravenously and when combined with the checkpoint blockade. Once the maximum tolerated dose is found for each of these groups, expansion cohorts will be initiated to further evaluate the safety and efficacy of VET3-TGI. The study is enrolling patients with pathologically confirmed, advanced, unresectable or metastatic solid tumors. “VET3-TGI has the potential to reshape our approach to treating advanced tumors and provide a new path forward for patients who urgently need better treatment options,” said Jorge Nieva, M.D., Associate Professor of Clinical Medicine at the Keck School of Medicine of the University of Southern California and Section Head of Lung and Head/Neck Tumors at the Norris Comprehensive Cancer Center and a member of KaliVir’s Medical Advisory Board. “This is a pivotal milestone and I look forward to seeing the continued progress of VET3-TGI as a monotherapy and in combination with checkpoint inhibitor therapy.” About KaliVir Immunotherapeutics, Inc. KaliVir Immunotherapeutics is a clinical-stage biotechnology company at the forefront of developing next-generation oncolytic immunotherapies. By harnessing the unique advantages of the vaccinia platform, KaliVir engineers optimized viral backbones to create innovative candidates for cancer treatment. The Company’s proprietary Vaccinia Enhanced Template (VET™) platform integrates multiple genetic modifications, allowing for the systemic delivery of oncolytic vaccinia candidates and the targeted expression of therapeutic transgenes within tumors. The Company is actively expanding its pipeline using the VET™ platform, with its capabilities validated through strategic global partnerships with Astellas Pharma and Roche. Currently, the Company has two product candidates in Phase 1 clinical trials: ASP1012, exclusively licensed and led by Astellas Pharma, and its internal lead candidate, VET3-TGI. With multiple therapeutic candidates progressing through clinical development, KaliVir is positioned as a leader in innovative cancer therapies. Headquartered in Pittsburgh, Pennsylvania, KaliVir is committed to revolutionizing cancer treatment. For more information, visit kalivir.com . SOURCE: KaliVir Immunotherapeutics